This is a revised application for a K23 Career Development award for Dr. Amit Shah, Assistant Professor of Epidemiology and Medicine at Emory University, and preventive cardiologist at the Atlanta VA Medical Center. Dr. Shah is establishing himself as a young investigator in patient-oriented clinical research. This K23 will provide Dr. Shah with support necessary to accomplish the following goals: (1) to become an expert in signal processing of electrocardiogram (ECG) data, including the use of custom and commercial software to derive heart rate variability (HRV), T-wave alternans (TWA), and spatial QRS-T angle (SA); (2) learn, through formal didactics and hands on experience, the necessary skills to evaluate genetic and ischemic determinants of arrhythmia risk due to acute emotional stress; and (3) learn core clinical research skills to plan and execute patient-oriented studies, including hands-on training with patients in the clinical research lab. Dr. Shah has assembled a mentoring team comprised of a primary mentor, Dr. Viola Vaccarino, Chair of Epidemiology, and renown expert on psychological risk factors of heart disease, and 2 co-mentors who are long-standing collaborators with Dr. Vaccarino, including Dr. Rachel Lampert, a Yale electrophysiologist who is an expert in emotional determinants of arrhythmia, and Dr. J Douglas Bremner (co-mentor), an Emory psychiatrist and radiologist with expertise in nuclear imaging and traumatic stress. The epidemiology, mechanisms, and therapies for emotionally-triggered arrhythmia are difficult to study because many ventricular arrhythmias are fatal. As a solution to this conundrum, Dr. Shah proposes to study surrogate ECG markers of arrhythmia during laboratory-induced acute mental stress in a large study of nearly 1,000 CHD patients led by his mentor, Dr. Vaccarino (R01 HL109413), and advisor, Dr. Quyyumi (P01 HL101398). In this well-characterized, genotyped and phenotyped cohort, he will study the relationships of autonomic modulation during stress and mental stress ischemia with arrhythmia risk during stress (T-wave alternans and spatial QRS-T angle) in Aim 1. Specifically, he will evaluate to what extent electrical instability may develop due to parasympathetic withdrawal (reduced HRV), and sympathetic activation (increased norepinephrine and vasoconstriction). To assess potential molecular targets and better risk stratify high-risk subjects, he will study select adrenergic/cholinergic genetic receptor polymorphisms that may influence electrical instability during mental stress (Aim 2). Finally, in aim 3, he will evaluate the prognostic value of stress reactivity based on autonomic and electrophysiologic measures under study towards major adverse cardiac events and death. Overall, this research will form the basis for larger studies that systematically evaluate risk prediction strategies and possible treatments such as cognitive therapy and biofeedback in CHD patients.